A protein kinase transmits signals related to proliferation, intercellular communication, survival and the like, by phosphorylating tyrosine, serine or threonine in the protein itself or in other proteins. Such signals take an important role in proliferation, survival and the like of normal cells. However, genetic mutation, overexpression or activation of a molecule having protein kinase activity in cancer cells causes uncontrollableness of the signals, and leads to abnormal accentuation of the signals. For example, receptor type tyrosine kinases such as EGFR, HER2, IGFR, PDGFR and the like, non-receptor type tyrosine kinases such as Src, FAK, Met and the like, and serine threonine kinase such as Akt, c-raf, MEK and the like are overexpressed or activated in cancer cells, and for example, tyrosine kinases such as EGFR, Ab1, F1t-3 and the like, and serine threonine kinase such as b-raf and the like are reported to have genetic mutations (Genes and Development, Vol. 17, p. 2998 (2003)). In addition, when the gene of such a protein kinase is transfected to normal cells and overexpressed, the cells turn into cancer cells. Tumor development, tumor growth and malignant alteration of tumor are closely related to the accentuation of signals by protein kinases. Accordingly, a compound inhibiting protein kinases is believed to be useful as a drug for the prophylaxis and/or treatment of cancer, due to the ability to inhibit the proliferation of cancer cells, or to block the survival signals, and the like.
Abnormal protein kinases are also involved in other various diseases, in addition to cancer. For example, arteriosclerosis is related to the signals from PDGF receptors, etc.; nephritis to the signals from PDGF receptors, etc.; multiple sclerosis to the signals from Lck, etc.; viral diseases such as AIDS to the signals from Mos, etc.; psoriasis to the signals form EGF receptors, etc.; diabetic retinopathy to the signals from VEGF receptors, etc.; rhinitis to the signals from Syk, etc.; asthma to the signals from Syk, JAK3, Iκκβ, etc.; glaucoma to the signals from ROCK, etc.; allergic diseases to the signals from Lyn, etc.; cardiac failure to the signals from ROCK, etc.; subarachnoid hemorrhage to the signals from ROCK or Rho, etc.; impotence to the signals from ROCK, etc.; Parkinson's disease to the signals from Jun, etc.; cerebral ischemic disease to the signals from Jun, Src, GSK-3, etc.; ischemic heart diseases such as myocardial infarction, angina pectoris and the like to the signals from p38MAP kinases, etc.; chronic rheumatoid arthritis to the signals from Iκκ1, etc.; thrombosis to the signals from PKC, etc.; obesity to the signals from GSK-3, VEGF receptors, etc.; diabetes mellitus to the signals from GSK-3, etc.; chronic obstructive lung disease to the signals from GSK-3, etc.; osteoporosis to the signals from Src, etc.; and the rejection response associated with transplantation to the signals from Lck, etc. Therefore, such compound inhibiting protein kinases is believed to be useful as a drug for the prophylaxis and/or treatment of these diseases.
The Src family members are non-receptor type tyrosine kinases consisting of at least 9 members (Src, Fyn, Yes, Blk, Yrk, Fgr, Hck, Lck and Lyn) (Annual Review of Cell Development and Biology, Vol. 13, p. 513 (1997)). Among these, Src is in particular highly related to cancer. For example, when the level of Src protein is reduced, tumor growth is inhibited (Cell Growth and Differentiation, Vol. 8, p. 269 (1997)), while when the level of Src protein is increased, tumor growth is accelerated (Cell Growth and Differentiation, Vol. 8, p. 1287 (1997)). Further, Src has increased activity in colon cancer, breast cancer, pancreatic cancer, ovarian cancer, esophageal cancer, lung cancer, cervical cancer, stomach cancer and the like (Biochimica et Biophysica Acta, Vol. 1602, p. 114 (2002)), and it is reported that cancer with activated Src is highly metastatic and shows poor prognosis (Cancer Research, Vol. 94, p. 344 (2002)). Moreover, when the level of Src protein is reduced in cancer cells, the amount of VEGF produced is decreased (Journal Biological Chemistry, Vol. 273, p. 1052 (1998)). Since Src is involved in the proliferation signals of VEGF in vascular endothelial cells (Molecular cell, Vol. 4, p. 915 (1999)), Src also plays an important role in angiogenesis. Therefore, Src promotes proliferation of cancer cells directly or through angiogenesis, and thus, a compound inhibiting Src is believed to be useful as a drug for the prophylaxis and/or treatment of cancer such as, for example, colon cancer, breast cancer, pancreatic cancer, ovarian cancer, esophageal cancer, lung cancer, cervical cancer, stomach cancer and the like.
In addition, a knock-out mouse lacking Src gene develops marble bones disease, which is a disease caused by the lack of osteoclast activity (Cell, Vol. 64, p. 693 (1991)). It has been found that in such a mouse, there is no change in the number of osteoclast cells, but the function thereof is impaired. Further, the Src expression is high in the osteoclast cells, and osteoporosis develops when the activity of osteoclast cells predominates over the activity of osteoblast cells. Accordingly, a compound inhibiting Src is believed to be useful as a drug for the prophylaxis and/or treatment of osteoporosis. Furthermore, since creation of space inside the bone where cancer cells can proliferate under the activation of osteoclast cells, plays an important role in osseous metastasis, a compound inhibiting Src can be used as a drug for the prophylaxis and/or treatment of osseous metastasis of cancer cells (Cancer Research, Vol. 63, p. 5028 (2003)).
For the literature describing kinase inhibitors, particularly Src inhibitors, for example, JP-A No. 2003 -519127, WO 03/004492, and WO 03/008409 may be mentioned.
Further, for the literature disclosing a compound similar to the pyrazoloquinolone derivative of the present patent application, for example, the following literatures are available.
EP-A No. 476544 describes a compound represented by the formula:
wherein R1, R2 and R3 are each a hydrogen atom or a lower alkyl group; R4 is a hydrogen atom, a lower alkyl group, a lower haloalkyl group, or a lower alkoxy-carbonyl group; and broken line represents two conjugated double bonds existing in the pyrazole ring,
or a salt thereof as a therapeutic agent for inflammation and hepatic failure.
JP-A No. 5-132484 describes a compound represented by the formula:
wherein R1 is a hydrogen atom, a lower alkyl group, a lower alkenyl group, a carboxy-lower alkyl group, a lower alkoxy-carbonyl-lower alkyl group, a halogen-substituted lower alkyl group, a phenyl-lower alkyl group, or a phenyl group which may be substituted with a group selected from a halogen atom and a lower alkoxy group; R2 is a hydrogen atom, a lower alkyl group, a phenyl group, a hydroxy-lower alkyl group, a cyano-lower alkyl group, a carboxy-lower alkyl group, a lower alkoxy-carbonyl-lower alkyl group, a halogen-substituted lower alkyl group, or a lower alkoxy-carbonyl group; R3 is a hydrogen atom, or a halogen atom; R4 and R5 may be identical or different, and are each a hydrogen atom, a lower alkanoyl group, a lower alkylsulfonyl group, a lower alkyl group, a lower alkenyl group, a formyl group or a carboxy-lower alkyl group; R2 and R4 may be bonded to each other to form the group —CH2—CH2—CO— or the group —CH═CH—; Y is the group —CH═ or a nitrogen atom; and broken line represents two double bonds existing in the pyrazole ring,
as an agent for the prophylaxis and/or treatment of chronic arthritic rheumatism, nephritis, psoriasis, systemic erythematosus, and low back pain.
WO 95/32205 describes a compound represented by the formula:
wherein R1 and R2 are each independently a hydrogen atom, a lower alkyl group, a lower alkoxy group or the like; and X is —CH═CH—, —NH— or the like,
as an agent for the prophylaxis and/or treatment of ischemia and hyperlipidemia.
WO 01/42247 describes a compound represented by the formula:
wherein A, B and D may be identical or different, and are each a nitrogen atom, an oxygen atom, a sulfur atom or the like; E and G may be identical or different, and are each a nitrogen atom, an oxygen atom, a sulfur atom or the like; J is a nitrogen atom, a substituted carbon atom or the like; K and L may be identical or different, and are each a carbon atom or a nitrogen atom; M is a hydrogen atom, a hydroxy group which may be substituted or the like,
as an agent for the prophylaxis and/or treatment of depression and mania.
It is strongly demanded to develop a compound which has excellent kinase inhibitory activity, particularly Src inhibitory activity, and which is useful as a medicine.